title: Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44.
abstract: The tumor microenvironment makes a decisive contribution to the development and dissemination of cancer, for example, through extracellular matrix components such as hyaluronan (HA), and through chemokines that regulate tumor cell behavior and angiogenesis. Here we report a molecular link between HA, its receptor CD44 and the chemokine CXCL12 in the regulation of cell motility and angiogenesis. High-molecular-weight HA (hHA) was found to augment CXCL12-induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility. The augmentation of CXCR4 signaling translated into increased vessel sprouting and angiogenesis in a variety of assays. Small HA oligosaccharides (sHA) efficiently inhibited these effects. Both siRNA-mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12-induced CXCR4 signaling depends on the binding of hHA to CD44. Consistently, CD44 and CXCR4 were found to physically interact in the presence of CXCL12, an interaction that could be inhibited by sHA. These findings provide novel insights into how microenvironmental components interact with cell surface receptors in multi-component complexes to regulate key aspects of tumor growth and progression.
authors.affiliation: Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Karlsruhe, Campus North, Postfach 3640, Karlsruhe, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Fuchs
authors.forename: A
authors.initials: A
authors.lastname: Hippe
authors.forename: A
authors.initials: A
authors.lastname: Schmaus
authors.forename: B
authors.initials: B
authors.lastname: Homey
authors.forename: J P
authors.initials: JP
authors.lastname: Sleeman
authors.forename: V
authors.initials: V
authors.lastname: Orian-Rousseau
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008970:Molecular Weight; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054377:Chemokine CXCL12; D018960:Hyaluronan Receptors; D019718:Receptors, CXCR4; D006820:Hyaluronic Acid